System for delaying drug delivery up to seven hours

ABSTRACT

A dosage form is disclosed comprising means for delaying the delivery of drug from the dosage form following the administration of the dosage form to a patient in need of drug therapy.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 08/036,648 filedMar. 24, 1993 U.S. Pat. No. 6,146,662; which is a continuation of U.S.Ser. No. 07/971,011 filed Nov. 2, 1992 U.S. Pat. No. 5,252,338; whichapplication is a continuation of U.S. application Ser. No. 07/799,451,filed on Nov. 26, 1991, now U.S. Pat. No. 5,190,765 issued Mar. 2, 1993,which application Ser. No. 07/799,451 is a continuation-in-part of U.S.Ser. No. 07/722,622 filed Jun. 27, 1991, now U.S. Pat. No. 5,160,744issued Nov. 3, 1992, which applications are incorporated herein byreference and benefits are claimed of their filing dates. Theseapplications are assigned to the ALZA Corporation of California.

DISCLOSURE OF TECHNICAL FIELD

This invention pertains to a novel dosage form useful for delayed-drugdelivery. More specifically, the invention relates to a dosage form thatafter administration of the dosage form is followed by a drug-freeperiod, which dosage form at this later time delivers a dose of drug fordelayed therapy. The drug is delivered during the drug-delivery periodat a controlled rate over time. The invention pertains also to aninitial pulse of drug followed by a drug-free interval, which latterinterval is followed by a drug delivery period over time. The inventionconcerns also a method of delayed-drug therapy by administering a dosageform that delays the onset of drug delivery, and after the drug-freeinterval delivers a drug for its therapeutic effect.

DISCLOSURE OF BACKGROUND ART

A critical need exists for a dosage form that makes available at a latertime a drug to satisfy a therapeutic demand. The demand can arise duringa circadian or chronological cycle, or the demand can arise forproducing a therapeutic effect a later time, such as during the morninghours. For examples, many patients with myocardial infarction exhibit aclinical incidence of this syndrome that shows a circadian distributionwith high frequency in the morning hours between 4:00 a.m. and 9:00a.m., as reported in The American Journal of Cardiology, Vol. 62, pages635 to 637, 1988; Circulation, Vol. 82, pages 897 to 902, 1990; andHeart Disease, Vol. 2, pages 1234 to 1235, 1988. Yet, the medical art,previously lacked a dosage form for administering a drug that providestherapy for this application during these critical hours.

There are dosage forms known to the prior art for delivering a drugcontinuously over time, such as disclosed in U.S. Pat. No. 4,327,725issued to Cortese and Theeuwes, and in U.S. Pat. Nos. 4,612,00;4,765,989; and 4,783,337 issued to Wong, Barclay, Deters and Theeuwes.The dosage forms disclosed in these patents comprise a semipermeablewall that surrounds a compartment. The compartment comprises a drugformulation, and in contact with the drug formulation, a displacementmember that pushes the drug formulation from the dosage form. Thesedosage forms operate by imbibing fluid through the semipermeable wallinto the compartment, wherein the fluid contacts and motivates thedisplacement member to consume space and thereby pushes the drugformulation from the dosage form. These dosage forms operatesuccessfully for their intended use, and they can deliver many differentto deliver drugs for their intended purpose. One limitation, however,associated with these dosage forms, consists in the dosage formimmediate delivery of drug of a drug recipient. That is, the dosageforms do not provide for the delayed delivery of a drug to satisfy afuture therapeutic need.

It is immediately apparent in the light of the above presentation that apressing need exists for a dosage form that can delay the delivery of adrug to provide a drug-free interval and then deliver a dose of drug. Itwill be appreciated by those versed in the dispensing art, that if anovel and unique dosage form is made available for executing atherapeutic program comprising a drug-free interval followed by adrug-delivery interval, or a pulsed dose followed by drug-free time,followed by drug delivery time, such a delayed drug-delivery dosage formwould have a practical application, and it would also represent avaluable contribution to the medical arts.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a novel and useful dosage form thatrepresents an unexpected improvement in the dispensing art andsubstantially overcomes the disadvantages known to the prior art.

Another object of the present invention is to provide a dosage form thatcan delay the delivery of a beneficial drug.

Another object of the present invention is to provide a dosage form thatcan delay the delivery of the drug from the dosage form, and thendeliver a dose of the drug.

Another object of the present invention is to provide a novel dosageform comprising means for delaying the delivery of drug, followed bymeans for delivering at a later time a dose of drug.

Another object of the present invention is to provide a dosage form thatdelivery a pulsed dose of drug, followed by a drug-free interval,followed by a drug delivery interval to provide unexpected beneficialtherapy.

Another object of the present invention is to provide a novel dosageform comprising means for delaying the delivery of drug for 30 minutesup to 7.0 hours from a dosage form, usually 30 minutes to 4.5 hours.

Another object of the present invention is to provide a novel dosageform that overcomes the limited functionality of conventional dosagetablets, and which novel dosage form can perform a drug programcomprising a drug-free period for a duration as needed, and then toprovide a drug-delivery period as needed for a time to achieve a desiredtherapeutic program.

Another object of the invention is to provide a dosage form comprisingin a single dosage form a dosage of drug that is released by the dosageform at least two hours after the dosage form is administered to a drugrecipient, and then delivers a drug for a later therapeutic effect.

Another object of the present invention is to provide a novel dosageform manufactured in the form of a drug delivery device comprising meansfor providing a drug-free interval, and means for then providing afuture dose of drug.

Another object of the present invention is to provide a novel dosageform that makes available at a later time a drug for satisfying a needthat can arise during a circadian or chronological cycle, or forproviding a drug during the morning hours.

Another object of the invention is to provide a dosage form comprising awater-soluble, non-ionic polymer useful for providing delayed therapy.

Another object of the invention is to provide a therapeutic programcomprising an instant dose of drug, followed by a drug-free interval andthen a drug-delivery interval.

Another object of the invention is to provide morning therapy, alsoidentified as AM-therapy, for providing therapy on a patient awakeningand rising in the morning for good health.

Other objects, features and advantages of the invention will be moreapparent to those versed in the dispensing art from the followingspecification, taken in conjunction with the drawing figures and theaccompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

Drawing FIG. 1 is a general view of a dosage form provided by theinvention, which dosage form is designed and shaped for oraladministration, and for a delayed pattern of drug delivery to thegastrointestinal tract;

Drawing FIG. 2 is an opened view of the dosage form of FIG. 1 fordepicting the structure of the dosage form, wherein the wall of thedosage form comprises means for delaying the delivery of drug from thedosage form;

Drawing FIG. 3 is an opened view of the dosage form of FIG. 1, fordepicting the internal structure of the dosage form, wherein the dosageform comprises an internal coat for delaying drug delivery, which coatsurrounds a drug reservoir for delaying the delivery of drug from thereservoir of the dosage form;

Drawing FIG. 4 is an opened view of the dosage form of FIG. 1,comprising external means for delivering an immediate pulsed dose ofdrug followed by a drug-free interval and then a drug-delivery intervalfor a therapeutic effect; and,

Drawing FIG. 5 depicts the change in viscosity for a polymer in responseto fluid stress of increasing concentrations.

Drawing FIG. 6 illustrates the cumulative release profile for an osmoticdosage form of the present invention described in Example 10 noting thetime delay start up time, T_(D).

Drawing FIG. 7 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 10 through a single 25 milorifice.

Drawing FIG. 8 illustrates the cumulative amount released from anembodiment of an osmotic dosage form described in Example 10 through asingle 25 mil orifice.

Drawing FIG. 9 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 10 through four 25 milorifices.

Drawing FIG. 10 illustrates the cumulative amount released from anembodiment of an osmotic dosage form described in Example 10 throughfour 25 mil orifices.

Drawing FIG. 11 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 10 through four 25 milorifices.

Drawing FIG. 12 illustrates the cumulative amount released from anembodiment of an osmotic dosage form described in Example 10 throughfour 25 mil orifices.

Drawing FIG. 13 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 11 manufactured free of asubcoat.

Drawing FIG. 14 illustrates a comparison of the cumulative amountreleased from an embodiment of an osmotic dosage form described inExample 12 manufactured free of a subcoat with the cumulative amountreleased from an embodiment of an osmotic dosage form described inExample 12 manufactured comprising a subcoat.

Drawing FIG. 15 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 12 manufactured free of asubcoat.

Drawing FIG. 16 illustrates the cumulative amount released from anembodiment of an osmotic dosage form described in Example 12manufactured free of a subcoat.

Drawing FIG. 17 illustrates the release rate for an embodiment of anosmotic dosage form described in Example 12 manufactured comprising asubcoat.

Drawing FIG. 18 illustrates the cumulative amount released from anembodiment of an osmotic dosage form described in Example 12manufactured comprising a subcoat.

Drawing FIG. 19 illustrates the drug delay from an osmotic dosage formcomprising a subcoat for different subcoat weights as described inExample 12.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures areexamples of dosage forms provided by the invention, and which examplesare not to be construed as limiting, one example of a dosage form isseen in drawing FIG. 1. In drawing FIG. 1, a dosage form 10 is seencomprising a body member 11 comprising a wall 12, that surrounds aninternal structure not seen in drawing FIG. 1. Dosage form 10 comprisesat least one exit port 13 for connecting the exterior with the interiorof dosage form 10.

In drawing FIG. 2, dosage form 10 of FIG. 1 is seen in opened section.In drawing FIG. 2, dosage form 10 comprises a body 11, a wall 12 thatsurrounds and forms internal compartment 14, that communicates through apassageway 13 with the exterior of the dosage form 10. Wall 12 comprisesa semipermeable composition and it comprises wall forming means 15 fordelaying the delivery of drug 16 from compartment 14. Compartment 14contains a drug composition 16 comprising drug 16 and polymeric means 17for delaying the delivery of drug 16. Polymeric means 17 possesses aslow rate of hydration dependent on its high molecular weight andviscosity. The slow rate of hydration of internal polymeric means 17provides a corresponding slow rate of imbibition of fluid through wall12, to change the viscosity of means 17 from an essentiallynon-dispensable phase to a dispensable phase therapy providing a delayeddrug delivery followed by a drug-delivery period. Polymeric means 17operates in conjunction with wall-forming polymeric composition 15 inwall 12. The polymeric composition 15 in wall 12 possesses a slow rateof fluid hydration and this slow rate of hydration further slows therate of fluid imbibition through wall 12 by internal polymeric means 17by restricting fluid to polymeric means 17 and consequently its changein viscosity. The slow rate of hydration in wall 12 generally is from 15minutes to 3 hours in a presently preferred manufacture for 15 minutesto 2 hours. The combined operation of internal polymeric means 17 andwall-polymeric slow-rate of imbibition composition 15 produces adelayed-drug interval of at least two hours, or more.

Compartment 14 also houses a second or an osmotic composition 18 that isdistant from passageway 13 and in contacting relation with the first ordrug 16 composition. The second composition 18 contributes a drivingforce that acts in cooperation with the first or drug 16 composition fordelivering the preferred therapeutic amount of drug 16 during the drugdelivery interval from dosage form 10. The second composition 18comprises an optional osmagent 19 represented by dash lines, that issoluble in fluid imbibed into compartment 14, and they exhibit anosmotic pressure gradient across semipermeable wall 12 against anexternal fluid. The osmagent in another manufacture is blended with anosmopolymer 20, which osmopolymer 20 imbibes fluid into compartment 14and it exhibits an osmotic pressure gradient across semipermeable wall12 against an external fluid. The osmopolymer 20 and osmagent 19 arehydrophilic water-loving osmotically effective agents, and they possessosmotic properties such as the ability to imbibe external fluid throughsemipermeable wall 12. They exhibit an osmotic pressure gradient acrossthe semipermeable wall against the external fluid, and they occupy spacefor pushing the drug composition by space displacement through exitports 13. The osmagent 19 is preferably mixed with osmopolymer 20 forimbibing the optimal maximum volume of external fluid into compartment14. The imbibed fluid is available to optimize the volumetric rate andfor expansion of the second composition.

Drawing FIG. 3 illustrates another manufacture provide by the invention.Drawing FIG. 3 depicts dosage form 10 comprising body 11, wall 12comprising chemical means 15 for slowing the rate of fluid imbibitionthrough wall 12 into compartment 14, drug 16 in compartment 14,polymeric viscosity governing means 17 in compartment 14, and secondcomposition 18, which composition 18 comprises at least one of a memberselected from the group consisting of osmagent 19 and osmopolymer 20.Dosage form 10, in drawing FIG. 3, comprises a layer 21 that surroundsthe drug 16 composition and the osmotic 18 composition. Layer 21 ispositioned between the inside of wall 12 and the drug 16 composition andthe osmotic 18 composition. Layer 21 comprises a polymer that possessesa resistance to take-up water, and it slows or delays the rate of fluidimbibition into compartment 14. The physics-chemical action of layer 21thereby contributes to the delayed-delivery of drug 16 from dosage form10.

Drawing FIG. 4 illustrates another manufacture provided by the presentinvention. In drawing FIG. 4, dosage form 10 comprises an exterior coat22 that comprises a dosage unit amount of drug 16 for an initial pulsedose of drug 16 prior to a drug-free interval. The initial pulse is afirst dose of drug 16 followed by a drug-free interval, which latterinterval is followed by a drug-delivery interval. Exterior coat 22comprises from about 0.1 to 99.9 weight percent (wt %) of a drug, andfrom 99.9 to 0.1 wt % of a pharmaceutically acceptable carrier for thedrug. The total weight percent of all the coat-forming ingredient isequal to 100 wt %. In a more preferred embodiment the initial pulse doseof drug 16 is from 1 to 85 wt % and from 99 to 15 wt % of thepharmaceutically acceptable carrier. The carrier is a means forreleasably coating the drug onto the exterior surface of wall 12. In afluid environment of use, the carrier releases the drug 16 therebyproviding the initial or pulsed dose of drug. The coat 22 releases theinitial pulsed dose in from greater than zero time, usually 2.5 minutesup to 1 hour, and in a preferably preferred pulsed dose time of fromseveral minutes, more specifically from 5 minutes, up to 30 minutes.

The dosage form 10 of drawing FIGS. 1 through 4 can be used fordelivering drugs for their therapeutic benefit. The dosage forms 10 cantake a wide variety of shapes, sizes and forms adapted for delivering adrug to the environment of use. For example, the dosage forms includeoral, buccal, sublingual, intrauterine, vaginal, anal-rectal, andartificial glands dosage forms.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention it has now been foundthat a dosage form 10 can be manufactured with a first composition and adifferent second composition mutually housed in cooperative relationshipin the compartment of the dosage form. The dosage form comprises a wallthat defines a compartment. The wall comprises a composition that doesnot adversely affect the beneficial drug, osmagent, osmopolymer, and thelike. The wall is permeable, that is the wall is permeable to thepassage of an external fluid such as water and biological fluids, and itis substantially impermeable to the passage of drugs, osmagents,osmopolymers, and the like. The wall comprises a composition that doesnot adversely affect an animal, or host, or the components comprisingthe dosage form. The selectively semipermeable compositions used forforming the wall are non-erodible and they are insoluble in fluids.Typical compositions for forming the wall are, in one embodiment, amember selected from the group consisting of cellulose esters, celluloseethers and cellulose ester-ethers. These cellulosic polymers have adegree of substitution, D.S., on the anhydroglucose unit, from greaterthan 0 up to 3 inclusive. By degree of substitution is meant the averagenumber of hydroxyl groups originally present on the anhydroglucose unitcomprising the cellulose polymer that are replaced by a substitutinggroup. Representative materials include a member selected from the groupconsisting of cellulose acylate, and cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di-, and tricellulose alkanylates, mono-, di-, andtricellulose aroylates, and the like. Exemplary polymers includecellulose acetate having a D.S. up to 1 and an acetyl content up to 21%;cellulose acetate having an acetyl content of 32 to 39.8%; celluloseacetate having a D.S. of 1 to 2 and an acetyl content of 21 to 35%;cellulose acetate having a D.S. of 2 to 3 and an acetyl content of 35 to44.8%, and the like. More specific cellulosic polymers include cellulosepropionate having a D.S. of 1.8 and a propyl content of 39.2 to 45% anda hydroxyl content of 2.8 to 5.4%; cellulose acetate butyrate having aD.S. of 1.8, an acetyl content of 13 to 15% and a butyryl content of 34to 39%; cellulose acetate butyrate having an acetyl content of 2 to 29%,a butyryl content of 17 to 53% and a hydroxyl content of 0.5 to 4.7%;cellulose triacylates having a D.S. of 2.9 to 3, such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, cellulosetrisuccinate, and cellulose trioctanoate; cellulose diacylates having ofD.S. of 2.2 to 2.6, such as cellulose disuccinate, cellulosedipalmitate, cellulose dioctanoate, cellulose dipentanoate, co-esters ofcellulose, such as cellulose acetate butyrate and cellulose acetatepropionate.

Additional polymers useful for manufacturing the wall comprise ethylcellulose of various degree of etherification with ethoxy content offrom 40 to 55%, acetaldehyde dimethylcellulose acetate, celluloseacetate ethyl carbamate, cellulose acetate methyl carbamate, celluloseacetate diethyl aminoacetate, semipermeable polyamides; semipermeablepolyurethanes; semipermeable sulfonated polystyrenes; semipermeablecross-linked selective polymers formed by the coprecipitation of apolyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;3,276,586; 4,541,005; 3,541,006, and 3,546,142; semipermeable polymersas disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132;semipermeable lightly cross-linked polystryene derivatives;semipermeable cross-linked poly(-sodium styrene sulfonate);semipermeable cross-linked poly(vinylbenzyltrimethyl ammonium chloride);semipermeable polymers exhibiting a fluid permeability of 2.5×10⁻⁸ to2.5×10⁻⁴ (cm²/hr.atm) expressed per atmosphere of hydrostatic or osmoticpressure difference across the semipermeable wall. The polymers areknown to the art in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020;and in Handbook of Common Polymers, by Scott J. R. and Roff, W. J.,1971, published by CRC Press, Cleveland, Ohio.

The polymeric composition 15 present in wall 12 for slowing or fordelaying the rate of passage of a fluid, such as water or a biologicalfluid through wall 12 comprises a polymer exhibiting a 8,500 to4,000,000 molecular weight, and present in wall 12 in a concentration of15 wt % to 85 wt %. Polymeric materials, operable for the presentpurpose, consist of member selected from the group consisting of anon-ionic water-soluble polymer, cellulose ether nonionic with itssolution unaffected by cations, hydroxyalkylcellulose,hydroxyalkylalkylcellulose, hydroxypropylcellulose, phenylcellulose,benzylcellulose, nonionic cellulose ester with its solutions unaffectedby cations, benzhydryllcellulose, hydroxyethyloctylcellulose,diphenylmethylcellulose, hydroxyethylcellulose, tritylcellulose andpolymer compositions that delay water flux up to 7.0 hours, and morepreferably, up to 4.5 hours.

Carrier member 22 used for containing exterior drug 16 in drug-releasingrelation, which carrier member 22 is positioned on the exterior surfaceof wall 12 comprises a member selected from the group consisting ofhydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxybutylcellulose, hydroxypentylcellulose,hydroxypropylmethylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose. Carrier22, when present, is from 0.1 mm to 10 mm thick, for providing a dose ofdrug.

Layer 21 is initial contacting relation with the internal surface ofsemipermeable wall 12 and in initial contacting relation with drug 16composition and with push 18 composition, comprises a layer 21, 0.1 mmto 15 mm thick. Layer 21 comprises a member selected from the groupconsisting essentially of hydroxyalkylcellulose,hydroxyalkylalkylcellulose, nonionic water-soluble polymers, celluloseesters nonionic with its solutions unaffected by cations, celluloseethers nonionic with its solution unaffected by cations,hydroxyethylcellulose, hydroxyethylpentylcellulose,hydroxyethyloctylcellulose, hydroxypropylcellulose,hydroxyalkylarylcellulose, hydroxyphenylcellulose, phenylcellulose,benzylcellulose, benzhydrylcellulose, diphenylmethyl- cellulose andtritylcellulose. The polymer comprising layer 21 comprises a 8,500 to4,000,000 molecular weight. The cellulosic polymer comprising layer 21can be the same or different than the cellulosic polymer 15 present inwall 12.

In the specification and the accompanying claims, the term “drug 16”includes any physiologically or pharmacologically active substance thatproduces a local or systemic effect, in animals, including warm-bloodedmammals, humans and primates; avians; household, sport and farm animals;laboratory animals; fishes; reptiles and zoo animals. The term“physiologically”, as used herein, denote the administration of drug 16to produce generally normal levels and functions. The term“pharmacologically” denotes generally variations in response to theamount of drug administered to the host. See Stedman's MedicalDictionary, 1966, published by Williams and Wilkins, Baltimore, Md. Theterm “circadian”, as used herein, denotes a biological activity thatrecurs at intervals during a 24 hour period. The phrase “drugformulation”, as used herein, means the drug is in the compartment mixedwith means for delaying the delivery of drug 16 from dosage form 10. Thedrug 16 that can be delivered includes a member selected from the groupconsisting of inorganic and organic drugs without limitation includesdrugs that act on the peripheral nerves, adrenergic receptors,cholinergic receptors, nervous system, skeletal muscles, cardiovascularsystem, smooth muscles, blood circulatory system, synaptic sites,neuro-effector junctional sites, endocrine system, hormone systems,immunological system, reproductive system, skeletal system, autocoidsystems, alimentary and excretory systems, inhibitory of autocoidsystems, inhibitory of histamine system. The active drug, that can bedelivered for acting on these recipients, include a member selected fromthe group consisting of anticonvulsants, analgesics, antiparkinsons,anti-inflammatories, calcium antagonists, anesthetics, antimicrobials,antimalarials, antiparasites, antihypertensives, antihistamines,antipyretics, alpha-adrenergic agonist, alpha-blockers, biocides,bactericides, bronchial dilators, beta-adrenergic blocking drugs,contraceptives, cardiovascular drugs, calcium channel inhibitors,depressants, diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, ophthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins,nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes,polypeptide drugs, and the like.

Drug 16, that can be dispensed by dosage form 10, is represented by amember selected from the group of a calcium channel blocker such asnifedipine, isradipine, nilvadipine, verapamil, flunarizine, nimodipine,diltiazem, nicardipine, norverapamil, nitredipine, nisoldipine,felodipine, amlodipine, cinnarizine and fendiline. Drug 16, that alsocan be dispensed by dosage form 10, is represented by an angiotensinconverting enzyme inhibitor selected from the group consisting ofangiotensin converting enzyme inhibitors that are essentially-free ofsulfur, angiotensin converting enzyme inhibitors containing a sulfhydrylgroup, angiotensin converting enzyme inhibitors containing a linearsulfide, angiotensin converting enzyme inhibitors containing a cyclicsulfide, and angiotensin converting enzyme inhibitors containing amethysulfonyl group. Representation of angiotensin converting enzymeinhibitors are more specifically represented by a member selected fromthe group consisting of ramipril, fosinopril, altiopril, benzaepril,libenzapril, alacepril, cilazapril, cilazaprilat, perindopril,zofenopril, enalapril, lisinopril, imidapril, spirapril, rentiapril,captopril, delapril, alindapril, indolapril, and quinapril. The amountof beneficial drug in a dosage form generally is about from 0.05 ng to1.5 g or more, with individual dosage forms containing, for example, 25ng, 1 mg, 5 mg, 10 mg, 25 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1.0 g or1.2 g. The beneficial drugs are known to the art in PharmaceuticalSciences, 14th Ed., edited by Remington, (1979) published by MackPublishing Co., Easton, Pa.; The Drug, The Nurse, The Patient, IncludingCurrent Drug Handbook, by Falconer, et al., (1974-1976), published bySaunders Company, Philadelphia, Pa.; Medicinal Chemistry, 3rd Ed., Vol.1 and 2, by Burger, published by Wiley-Interscience, New York; and inPhysician's Desk Reference, 38 Ed., (1984), published by MedicalEconomics Co., Oradell, N.J.

The drug can be in various forms, such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as inorganic,organic, hydrochloride, hydrobromide, sulfate, laurate, palmitate,phosphate, nitrite, borate, acetate, maleate, tartrate, oleate andsalicylate. For acidic drugs, salts or metals, amines or organiccations; for example, quaternary ammonium can be used. Derivatives ofdrugs, such as esters, ethers and amides, can be used as represented by,for example, hydroxy, lower alkoxy, lower alkenoxy, diloweralkylaminolower alkoxy (for example, dimethylaminoethoxy), acylamino lower alkoxy(for examples, acetylaminoethoxy), acyloxy lower alkoxy (for example,pivaloyloxyethoxy), aryloxy (for example, phenoxy), arylloweralkoxy (forexample, benzyloxy), amino, lower alkylamino, diloweralkylamino,hydroxyamino, aryllower alkylamino (for example, benzylamino), orsubstituted aryloxy or substituted arylloweralkoxy wherein thesubstituent is methyl, halo or methoxy.

Polymeric viscosity governing means 17 blended with drug 16, is usefulfor producing a delay or drug-free interval, according to the mode andthe manner of the invention. The polymeric means 17 responds, when fluidstress is applied thereto, to a change from a delayed-drug free state toa dispensable drug delivery state. The change is accompanied by thepolymeric means imbibing fluid to increase its viscosity, that is, tochange from a non-fluid to a semifluid or viscous dispensable phase. Thechange can take from 30 minutes up to 4.5 hours, and in a more presentlypreferred embodiment, from 45 minutes up to 3 hours, thereby producingthe drug-free delay period. Representative of a polymeric means operablefor the purpose of this invention are polymers comprising a 50,000 to1,000,000 molecular weight and possess the ability to imbibe fluid forchanging over time from a delay to a dispensable state. In a presentpreferred embodiment, the first composition comprises 20 wt % to 50 wt %of polymeric means 17. The polymers in a 2 wt % to 9 wt % concentrationin water exhibit a viscosity at 25° C. of 45 to 10,000 cps(centipoises). More specifically, the presently preferred embodimentcomprises polyethylene oxide possessing a 250,000 to 350,000 molecularweight and a 600 to 1,200 viscosity range for a 5% solution at 25° C.cps. The viscosity range for a polymer comprising a 300,000 molecularweight that imbibes an aqueous fluid is seen in accompanying drawingFIG. 5. The polymeric means 17 inside compartment 14 operates inconjunction with polymer 15, in wall 12. Polymer 15 by slowing the fluidflux into compartment 14, limits the volume of aqueous or biologicalfluid available to polymer 17, thereby concomitantly contributing to thedelay interval provided by polymer 17. Polymer 15 and polymer 17 operatetogether in concert to provide a delay of 30 minutes to 4.5 hours fordosage form 10. Viscosity measurements can be made according to theprocedures described in Chemical Dictionary, Fifth Ed., by Grant, page621, (1987), published by McGraw Hill Inc.; Encyclopedia of Chemistry,Fourth Edition, pages 822 to 826, (1984), published by Van NostrandReinhold Inc.; and in Pharmaceutical Sciences, by Remington, 17thEdition, pages 330 to 345, (1985), published by Mack Publishing Co.

The drug composition comprising drug 16 and polymeric means 17optionally comprises from 0 to 20 wt % of an osmagent. The osmagents areknown also as osmotically effective solutes, and they are known asosmotically effective compounds. They are soluble in fluid that entersdosage form 10, and they exhibit an osmotic pressure gradient acrosssemipermeable wall 12 against an exterior fluid. Representative of anosmagent, as seen in drawing FIG. 2, as circle 23, comprise a memberselected from the group consisting of water-soluble salts, magnesiumsulfate, magnesium chloride, sodium chloride, lithium chloride,potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate andwater-soluble sugars. The drug composition comprises an optional binder24, seen in drawing FIG. 2, as a vertical line. The concentration ofbinder 24 is from 0 wt % to 20 wt %, more preferably from 0.001 wt % to10 wt %. Representative of a specific binder for holding the drugcomposition in core formation, is polyvinylpyrrolidone having amolecular weight of 35,000 to 45,000, usually 38,000 to 40,000. The drugcomposition comprises 0 wt % to 3.5 wt % of a lubricant, such asmagnesium stearate, calcium stearate or stearic acid.

Osmotic composition 18, the second composition in the osmotic dosageform, comprises an osmopolymer 20. The osmopolymer exhibits fluidabsorbing and/or fluid imbibing properties. The osmopolymer comprises ahydrophilic polymer that can interact with water and aqueous biologicalfluids and then swell or expand to an equilibrium state. The osmopolymerexhibits the ability to retain a significant portion of the imbibed orabsorbed fluid. In operation, the drug composition and osmoticcomposition 18 cooperate to deliver drug 16 from dosage form 10. Inoperation, osmotic composition 18 absorbs fluid, expands and exertspressure against the drug composition. The osmopolymers swell or expandto a very high degree, usually to a 2 to 50 fold increase in volume.Representative of osmopolymers consists of a member selected from thegroup consisting of poly(hydroxyalkyl methacrylate) having a molecularweight of 20,000 to 5,000,000; poly(vinylpyrrolidone) having a molecularweight of about 10,000 to 350,000; poly(vinyl alcohol) having a lowacetate content and lightly cross-linked with glyoxal, formaldehyde,glutaraldehyde and having a degree of polymerization from 2,000 to30,000; poly(ethylene oxide) having a molecular weight from 10,000 to7,800,000; acidic carboxy polymers known as carboxypolymethylene or ascarboxyvinyl polymers, a polymer consisting of acrylic acid lightlycross-linked with polyallylsucrose and sold under the trademarkCarbopol®, acidic carboxy polymer having a molecular weight of 200,000to 6,000,000, including sodium acidic carboxyvinyl hydrogel andpotassium acidic carboxyvinyl hydrogel; Cyanamer® polyacrylamide; andthe like. The representative polymers, used for the purpose of thepresent invention, are known to the art in Handbook of Common Polymers,by Scott and Roff, published by the Chemical Company, Cleveland, Ohio;ACS Symposium Series, No. 31, by Ratner and Hoffman, pp. 1 to 36,(1976), published by the American Council Society; and in RecentAdvances in Drug Delivery Systems, by Schacht, pp. 259 to 278, publishedby Plenum Press, N.Y. The concentration of osmopolymer present inosmotic composition 18 is from 60 wt % to 85 wt %. Osmotic composition18 comprises from 2 wt % to 15 wt % of a hydroxypropylalkylcellulosepossessing a 9,000 to 25,000 molecular weight and consisting of a memberselected from the group consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropylbutylcellulose andhydroxypropylpentylcellulose. Osmotic composition 18 optionallycomprises 0.01 to 3.5 wt % of a lubricant, from 0.20 wt % to 2.0 wt % offerric oxide, and from 15 wt % to 30 wt % of an osmagent. The totalweight percent of all ingredients in the osmotic composition is equal to100 wt %. Osmotically effective osmagents, useful for the presentpurpose of providing osmotic composition 18, include magnesium sulfate,magnesium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium sulfate, sodium carbonate, lithium sulfate, sodiumsulfate, and the like. The osmagent is usually present as a particle,powder, granule, or the like. The osmotic pressure in atmospheres, ATM,of the osmagent suitable for the invention will be greater than zeroATM, generally from zero ATM up to 500 ATM, or higher. The osmoticpressure of an osmagent is measured in a commercially availableosmometer that measures the vapor pressure difference between pure waterand the solution to be analyzed, and according to standard thermodynamicprinciples the vapor pressure ratio is converted into an osmoticpressure difference. The osmometer used from the present measurements isidentified as Model 1001-A Vapor Pressure Osmometer, manufactured byKnauer and distributed by Utopia Instrument Co., Joliet, Ill.

The expression “exit means 13” as used herein comprises means andmethods suitable for releasing drug from compartment 14. The expressionincludes at least one passageway or orifice that passes through wall 12for communicating with compartment 14. The expression “at least onepassageway” includes aperture, orifice, bore, pore, porous elementthrough which drug can migrate, a hollow fiber, capillary tube and thelike. The expression includes also a material that erodes or is leachedfrom wall 12 in the fluid environment of use to produce at least onepassageway in the dosage form. Representative materials suitable forforming at least one passageway, or a multiplicity of passagewaysinclude an erodible poly(carbonate), poly(glycolic), or poly(lactic)acid member in the wall, a gelatinous filament, leachable materials suchas fluid removable pore forming polysaccharides, salts or oxides, andthe like. A passageway or a plurality of passageways can be formed byleaching a material such as sorbitol from the wall to produce acontrolled release pore-passageway. The passageway can have any shape,such as round, triangular, elliptical, and the like. The dosage form canbe constructed with one or more passageways in spaced apart relation onmore than a single surface of a dosage form. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,916,899;4,063,064; and 4,088,864. Pore-passageways of controlled dimensionsformed by leaching are disclosed in U.S. Pat. No. 4,200,098.

The wall 12 of the dosage form 10 and the exterior coat 22 can be formedin one technique using the air suspension procedure. This procedureconsists in suspending and tumbling delayed, bilayer compositions in acurrent of air and a wall forming or outer coat composition, until ineither operation the wall or the coat is applied to the delayed bilayercompositions. The air suspension procedure is well-suited forindependently forming the wall of the dosage form. The air suspensionprocedure is described in U.S. Pat. No. 2,799,241; in J. Am. Pharm.Assoc., Vol. 48, pp. 451 to 459, (1959); and, ibid, Vol. 49, pp. 82 to84, (1960). Osmotic systems 10 can also be coated with the wall formingcomposition, or the composition can be formed with a Wurster® airsuspension coater, using for example, methylene dichloride—methanol as acosolvent. An Aeromatic® air suspension coater can be used employing acosolvent. Other coating techniques, such as pan coating, can be usedfor providing the wall of the dosage form. In the pan coating system thewall 12 forming, or the exterior coat 22 are deposited by successivespraying of the composition on the delayed compositions, accompanied bytumbling in a rotating pan. A pan coater is used because of itsavailability at commercial scale. Other techniques such as airsuspension can be used for coating the drug core. An interposed layer,or an external coat can be applied by press coating during themanufacture of the dosage form. Finally, the wall or coated dosage formare dried in a forced air oven at 40° C. for a week, or in a temperatureand humidity controlled oven for 24 hours at 40° C. and 50% relativehumidity, to free the dosage form of solvent. Generally, the wall formedby these techniques has a thickness of 2 to 20 mils with a presentlypreferred thickness of 4 to 10 mils. The exterior coated dose 22 laminagenerally will have a thickness of 0.5 to 15 mils, usually 0.5 to 7.5mils.

Exemplary solvents suitable for manufacturing wall 12 or coat 22 includeinert inorganic and organic solvents that do not adversely harm thewall, the lamina and the final dosage system. The solvents broadlyinclude a member selected from the group consisting of an alcohol,ketone, ester, ether, aliphatic hydrocarbon, halogenated solvents,cycloaliphatic solvents, aromatic heterocyclic, aqueous solvents, andmixtures thereof.

The dosage form 10 of the invention is manufactured by standardtechniques. For example, in one manufacture, the beneficial drug andother ingredients comprising the first layer facing the exit means areblended and pressed into a solid layer. The layer possesses dimensionsthat correspond to the internal dimensions of the area the layer is tooccupy in the dosage form and it also possesses dimensions correspondingto the second layer for forming a contacting arrangement therewith. Thedrug and other ingredients can be blended also with a solvent and mixedinto a solid or semisolid form by conventional methods, such asballmilling, calendering, stirring or rollmilling, and then pressed intoa preselected shape. Next, a layer of osmopolymer composition is placedin contact with the layer of drug in a like manner. The layering of thedrug formulation and the osmopolymer layer can be fabricated byconventional two-layer press techniques. The two contacted layers arefirst coated with an outer wall 12. The drug composition over outersurface of wall 12 can be applied by press coating, molding, spraying,dipping, and air suspension procedures. The air suspension and airtumbling procedures comprises in suspending and tumbling the pressed,contacting first and second layers in a current of air containing thedelayed-forming composition until the first and second layers aresurrounded by the wall composition.

In another manufacture, dosage form 10 is manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the first layer or drug composition, areblended using an organic solvent, such as denature anhydrous ethanol, asthe granulation fluid. The ingredients forming the first layer or drugcomposition are individually passed through a 40 mesh screen and thenthoroughly blended in a mixer. Next, other ingredients comprising thefirst layer can be dissolved in a portion of the granulation fluid, thesolvent described above. Then, the latter prepared wet blend is slowlyadded to the drug blend with continual mixing in the blender. Thegranulating fluid is added until a wet blend is produced, which wet massblend is then forced through a 20 mesh screen onto oven trays. The blendis dried for 18 to 24 hours at 24° C. to 35° C. in a forced air oven.The dried granules are then sized with a 20 mesh screen. Next, magnesiumstearate is added to the drug screened granulation, is then put intomilling jars and mixed on a jar mill for 10 minutes. The composition ispressed into a layer, for example, in a Manesty® press. The speed of thepress is set at 20 rpm and the maximum load set at 2 tons. The firstlayer is pressed against the composition forming the second layer andthe bilayer tablets are fed to the Kilian® dry Coata press andsurrounded with the drug-free coat followed by the exterior wall solventcoating.

Another manufacturing process that can be used for providing thecompartment-forming composition comprises blending the powderedingredients in a fluid bed granulator. After the powdered ingredientsare dry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders are then dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant such as stearic acid ormagnesium stearate is mixed into the granulation, using a V-blender. Thegranules are then pressed in the manner described above.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomemore apparent to those versed in the art in the light of the presentdisclosure, the drawing figures and the accompanying claims.

Example 1

A dosage form for the controlled delivery of verapamil, comprisingadministering a dosage form at bedtime for releasing verapamil tocoincide with the early morning rise of blood pressure associated withhypertension and angina, is prepared as follows: first, 600 g ofverapamil hydrochloride, 305 g of poly(ethylene oxide) having amolecular weight of 300,000, and 40 g of sodium chloride (powder) werescreened through a 40 mesh stainless steel screen and blended with 50 gof polyvinylpyrrolidone, having a molecular weight of 38,000, for 15minutes in a blender to produce a homogenous mix. Then, a granulatingfluid, comprising 350 ml of anhydrous ethyl alcohol, is gradually addedinto the blended ingredients to produce a wet mass. The wet mass isdried at about 25° C., room temperature, for 16 hours. The dry granulesare then passed through a 16 mesh stainless steel screen. Next, 5 g ofmagnesium stearate is screened through an 80 mesh screen, and thescreened granules added to the blended mix and all the ingredientsblended in a blender for 2 minutes. This procedure provides the drugcomposition for providing the drug layer of the reservoir.

The osmotic composition designed for preparing the push layer is made asfollows: first, 735 g of polyethylene oxide, having a 7,000,000molecular weight, 200 g of sodium chloride, 50 g ofhydroxypropylmethyl-cellulose, with a viscosity of 5 cps, and 10 g ofred ferric oxide, were screened through a 40 mesh screen and blended for15 minutes to produce a homogenous mix. Next, 700 ml of anhydrous ethylalcohol is gradually added to the blended ingredients during blendinguntil a wet granulation is obtained. The wet granulation is thenmanually screened through the 20 mesh screen and dried at 25° C. for 16hours. The dry granules are then passed through a 16 mesh screen. Then,5 g of magnesium stearate, which is prescreened through an 80 meshscreen, is then added to the granules and mixed in a blender for 2minutes. Next, a drug composition, pressed into a layer, is provided asfollows:

COMPONENTS WT % MG/DOSAGE FORM DRUG COMPOSITION Verapamil HCL 60.0 198.0Polyox ® N-750 30.5 100.7 PVP K29-32 5.0 16.5 NaCl 4.0 13.2 Mg Stearate0.5 1.7 OSMOTIC COMPOSITION Polyox ®-303 73.5 80.9 NaCl 20.0 22.0 HPMCE-5 5.0 5.5 Fe₂O₃ 1.0 1.1 Mg Stearate 0.5 0.6

The abbreviation “Polyox N-750” denotes polyethylene oxide of 300,000molecular weight. “HPMC E-5” denotes hydroxypropylmethylcellulose of11,200 molecular weight, “Polyox-303” indicates polyethylene oxide of7,000,000 molecular weight, and “PVP K29-32” denotespolyvinylpyrrolidone of 38,000 molecular weight.

Next, a wall forming composition comprising 55 wt % cellulose acetate,comprising a 39.8% acetyl content, 40 wt % hydroxypropylcellulose and 5wt % polyethylene glycol—3350 are dissolved in 80% acetone and 20%methanol was coated around the bilayer core, using a pan coater. A wallweighing 118 mg per dosage form is applied to provide the delayedrelease dosage form.

Two 30 mil orifices were drilled on the drug composition side of thedosage form. The dosage form exhibited an in vitro 1.5 hours drug-freeinterval followed by delivering the verapamil drug at a controlledrelease rate of 20 mg/hour for 8 hours.

Example 2

The procedure of Example 1 is followed in this example, with allmanufacturing procedures and compositions as previously described,except that, in this example, the osmotic push composition is asfollows:

OSMOTIC COMPOSITION COMPONENTS WT % MG/DOSAGE FORM Polyox ®-303 73.5147.0 NaCl 20.0 40.0 HPMC E-5 5.0 10.0 Fe₂O₃ 1.0 2.0 Mg Stearate 0.5 1.0

Three 30 mil orifices were drilled on the drug side of each dosage form.The dosage form exhibited a 1 hour drug-free interval followed bydelivering 40 mg/hour of verapamil over 5 hours.

Example 3

An osmotic dosage form for the controlled and continuous release of acalcium channel blocker drug as exemplified by verapamil after aprogrammed delay of about 2 hours, was made as follows: first, 5,400 gof verapamil hydrochloride, 2,745 g of poly(ethylene oxide) of 300,000molecular weight, 225 g of polyvinylpyrrolidone of 38,500 molecularweight and 360 g of sodium chloride were passed through a 16 meshscreen. Next, the screened excipients were introduced into the fluid bedgranulator for 30 minutes and preheated to 35° C. A granulation solutionconsisting of 225 g of polyvinylpyrrolidone of 40,000 molecular weightdissolved in 2,588 g of distilled water was sprayed onto the fluidizedpowders in the granulator. Then, 45 g of magnesium stearate, which isprescreened through an 80 mesh screen, were added to the granules in amixer and the ingredients blended for 3 minutes.

An osmotic push composition was prepared in a similar manner. Thecomposition comprised 117,600 g of polyethylene oxide with a 7,500,000molecular weight, 32,000 g of sodium chloride, 3,200 g ofhydroxypropyl-methylcellulose of 11,200 molecular weight, and 1,600 g offerric oxide were screened through a 17 mesh screen. Next, the screenedingredients were introduced into a fluid bed granulator for 30 minutespreheated to 35° C. A granulating fluid consisting of 4,800 g ofhydroxypropyl-methylcellulose, of 5 cps viscosity dissolved into 55,200g of distilled water, was sprayed onto the fluidized ingredients.

Next, a bilayer core comprising a drug composition and a pushcomposition was prepared in a Manesty® Tablet Press. The bilayer coreswere surrounded with a cellulose acetate, hydroxypropylcellulose walland an orifice drilled through the wall is described in Example 1. Thedosage form after a 2 hour drug delay period delivers 21 mg/hour of drugover a prolonged period of time.

Example 4

The procedures described in the above examples are repeated in thisexample, with all the conditions as previously set forth, except that inthis example, the drug is a calcium channel blocking drug memberselected from the group consisting of nifedipine, isradipine,nilvadipine, flunarizine, nimodipine, diltiazem, nicardipine,nitredipine, nisoldipine, felodipine, amlodipine, cinnarizine andfendiline.

Example 5

The procedure described in the above examples is repeated in thisexample, with all the conditions as previously set forth, except that,in this example, the drug is an angiotensin converting enzyme inhibitorselected from the group consisting of alacipril, benazepril, cialzapril,captopril, delapril, enalapril, fosinopril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, and zofenopril.

Example 6

The dosage form prepared according to the above examples, wherein thedosage form is an osmotic delivery device comprising a caplet shape foreasy oral drug administration.

Example 7

In this example, the rate of hydration of (1) a wall compositioncomprising 60 wt % cellulose acetate consisting of 39.8% acetyl content,35 wt % polyvinylpyrrolidone of 38,000 molecular weight and 5 wt %polyethylene glycol 3350 is compared with the rate of hydration of (2) awall composition comprising 60 wt % cellulose acetate comprising a 39.8%acetyl content, 35 wt % hydroxypropylcellulose of 38,000 molecularweight and 5 wt % polyethylene glycol 3350. The composition (1)comprising polyvinylpyrrolidone hydrates quickly and lets fluid passinto the dosage form, while composition (2) comprisinghydroxypropylcellulose hydrates very slowly and substantially delays thepassage of fluid into the dosage form for 2 hours. The composition (2)operates with synergetic effect with the drug composition comprising apolymer of 250,000 to 350,000 molecular weight. Polymers of lowermolecular weight are substantially devoid of delay, which the polymerused by this invention exhibits a long delay prior to converting to adrug delivery phase.

Example 8

In this example, the above procedures are followed, with the addedmanufacture a hydroxyethylcellulose is interposed between the inside ofthe semipermeable wall and around the first or drug composition and thesecond or push composition. The interposed layer is about 6 mm thick andit slows or delays the rate of fluid imbibition into the first andsecond composition. The layer is applied as a dry composition by presscoating the layer in the interposed position. The layer also can beapplied by pan coating or air suspension coating. The procedure isrepeated using hydroxypropylcellulose as the interposed layer.

Example 9

The procedures of the above examples are repeated in this example, withthe added embodiment comprising the wall, which is coated on its outersurface with an exterior instant dose of verapamil hydrochloride blendedwith a quick-release, water-soluble polymer, such ashydroxypropylcellulose. The exterior instant dose is released in zero to40 minutes from the outer surface.

Example 10

An osmotic dosage form is prepared according to the procedure describedin Example 1. In this example, the physical-dynamic operation ismathematically described for the delayed drug delivery period for anosmotic system comprising a subcoat, free of drug, positioned in thecompartment between the semipermeable wall and surrounding the druglayer and the push layer. In the osmotic dosage form, the start-up time,T_(D), of a drug-delayed push-pull osmotic system with the interpositioned subcoat 21 is related to physically to the duration of aseries of hydration and transportation events leading to a steady-statedrug delivery period. The processes initiate with the hydration of thesemipermeable wall, followed by a transient expansion of the push-pullosmotic system to establish a steady-state outflow, and finally, thedelivery of the non-drug subcoat.

In the example, T_(D) is defined as the intercept on the time axis ofthe cumulative release profile as seen in FIG. 6: wherein, T_(D)comprises three terms, as defined in Eq. 1:

T _(D) =T ₁ −T ₂ −T ₃  (1)

wherein:

T₁=wall hydration,

T₂=hydration and water accumulation inside the expanded system beforesteady state delivery, and

T₃=subcoat hydration and delivery.

The hydration time of the semipermeable wall equals the “time-lag”expression describing diffusion of water through a semipermeablemembrane, which is defined by Eq. 2: $\begin{matrix}{T_{1} = \frac{h^{2}}{6D}} & (2)\end{matrix}$

wherein

h=membrane thickness, and

D=diffusivity of water in the semipermeable membrane

The transient time for a push-pull formulation to start-up involves thehydration and the establishment of the viscous flow of the drug layerformulation resulting in an expansion of the osmotic dosage form. Theprocess involves an in-flux of water to fill up the internal expansionof the osmotic system until steady-state delivery arrives, as set forthin Eq. 3: $\begin{matrix}{T_{2} = {K_{H}\left( \frac{\Delta \quad V}{Q} \right)}} & (3)\end{matrix}$

wherein

K_(H)=Hydration coefficient of the system,

ΔV=Volume change of the system between dry and steady-state release, and

Q=water influx rate.

In theory, the expansion in volume can be correlated with the pressuregenerated inside the dosage form before viscous flow occurs through theorifice or orifices.

The time for the subcoating 21 to be hydrated and delivered can beexpressed by Eq. 4: $\begin{matrix}{T_{3} = {{K_{H}^{\prime}\left( \frac{W_{D}f_{1}}{C_{C}^{\prime}} \right)}/Q}} & (4)\end{matrix}$

wherein

K′_(H)=Hydration coefficient of the subcoat,

W_(D)=Weight of the subcoat and f₁ is the fraction of the total subcoatbeing delivered, and

C′_(C)=Solid concentration of the hydrated subcoat during release.

Therefore, the total delay time, T_(D) can be expressed by Eq. 5.

T _(D) =T ₁ +T ₂ +T ₃  (1)

$\begin{matrix}\begin{matrix}{T_{D} = {T_{1} + T_{2} + T_{3}}} \\{= {\frac{h^{2}}{6D} + {K_{H}\left( \frac{\Delta \quad V}{Q} \right)} + {{K_{H}^{\prime}\left( \frac{W_{D}f_{1}}{C_{C}^{\prime}} \right)}\frac{1}{Q}}}}\end{matrix} & (5)\end{matrix}$

The influx of water can be related to the zero order rate of the dosagesystem as seen in Eq. (6) and (7), and further disclosed in DrugDelivery and Therapeutic System, Encyclopedia of PharmaceuticalTechnology, by Theeuwes, F., Wong, P., Yum, S.; Vol. 4, Dekke, 303,(1991). $\begin{matrix}{Z = {\frac{A}{h}K\quad \Delta \quad {\pi \cdot S}\quad \left( {{Soluble}\quad {Drug}} \right)}} & (6) \\{Z = {\frac{A}{h}K\quad \Delta \quad {{\pi (H)} \cdot C_{C} \cdot f}\quad \left( {{Insoluble}\quad {Drug}} \right)}} & (7)\end{matrix}$

wherein

Z=zero order release rate of the system,

KΔπ=D=Diffusivity of the semipermeable membrane,

S=Solubility of the drug,

C_(C)=Solid concentration of the released suspension,

f=Fraction of insoluble drug in drug layer of the push pull system, and

A and h=Area and thickness of the membrane,

Therefore, they can be expressed by Eq. (8) and Eq. (9): $\begin{matrix}{Q = {\frac{Z}{S}\quad \left( {{Soluble}\quad {drug}} \right)}} & (8)\end{matrix}$

 Q=Z/C _(C) f (Insoluble drug)  (9)

Substitute (8) and (9) into (5), and the semipermeable membrane weight,Wm=hAρ (ρ=density of the membrane), then, as expressed by Eq. 10 and Eq.11: $\begin{matrix}{T_{D} = {\frac{W_{M}S}{6Z\quad \rho} + {K_{H}\quad \frac{\Delta \quad {VS}}{Z}} - {\frac{K_{H}^{\prime}W_{D}f_{1}S}{{ZC}_{C}^{\prime}}\quad \left( {{soluble}\quad {drug}} \right)}}} & (10) \\{T_{D} = {\frac{W_{M}C_{C}f}{6Z\quad \rho} + {K_{H}\quad \frac{\Delta \quad {VC}_{C}f}{Z}} - {\frac{K_{H}^{\prime}W_{D}f_{1}C_{C}f}{{ZC}_{C}^{\prime}}\quad \left( {{Insoluble}\quad {drug}} \right)}}} & (11)\end{matrix}$

Equations (10) and (11) consist of all measurable quantities exceptK_(H) and K′_(H), the hydration coefficients. If the hydration processis fast, they should have values close to unity; otherwise, they shouldbe greater than one. It is further observed the expression of T_(D) isinversely proportional to Z or proportional to T₉₀, time to deliver 90%of the dosage form.

Table I, presented hereafter, tests the actual delay time in comparisonto the calculated composite delays for T₁, T₂, and T₃. When thecomposite delays are calculated from experimental data on the push-pullosmotic system with an insoluble drug using Eq. 11, the observationsthat emerge after the comparison are as follows:

(a) There is good agreement between calculated and actual T_(D).

(b) T₁, the membrane hydration time is relatively short in the order offraction of an hour, and to design a delay utilizing the thickness ofmembrane as the principle factor is not a viable choice.

(c) T₂ and T₃ are major contributors to the total delay.

(d) K_(H) and K′_(H), the hydration coefficients of the core and thesubcoat have values very close to unity, implying the hydration is arapid process.

(e) f₁, the fraction of subcoat being delivered before the drugappeared, is about 0.5 for the push-pull system with orifice drilledonly on the drug layer. This coincides with our observation on therelease of the delayed osmotic push-pull system.

(f) The assumption of C_(C)=C′_(C) is reasonable if the viscosity of thedrug core and the subcoat is not drastically different.

Thus, the equation of delay time for the insoluble drug can besimplified further to Eq. (12): $\begin{matrix}{T_{D} = {\frac{W_{M}C_{C}f}{6Z\quad \rho} + \frac{\Delta \quad {VC}_{C}f}{Z} + \frac{0.5\quad W_{D}f}{Z}}} & (12)\end{matrix}$

All variables in Eq. (12) can be experimentally measured.

TABLE I COMPARISON BETWEEN EXPERIMENTAL DRUG-DELAY AND CALCULATEDDRUG-DELAY FROM EQ. 12 T. ΔV T₂ T₃ T₁ + T₂ T₁ + T₂ + T₃ T_(D (Actual))Push-Pull Osmotic System (hr) (μl) (hr) (hr) (hr) (hr) (hr) NicardipineInsoluble 0.18 58 2.2 — 2.4 — 2.6 Drug inside system without subcoat(FIG. 7) Verapamil Insoluble 0.15 56 1.2 — 1.4 — 1.5 Drug inside thesystem without subcoat (FIG. 9) Verapamil Soluble 0.18 102 1.9 2.8f₁ 2.12.1 + 2.8f₁ = 3.5 3.5 Drug inside system @ f₁ = 0.5 with subcoat (FIG.11)

wherein:

ρ=1.2 g/ml,

C_(C)≅C′_(C)≅0.6 g/ml,

K_(H)=K′_(H)≅1, and

ΔV=Experimental volume expansion values at the end of delay period.

In Table I, the osmotic system represented by FIG. 7 comprises a drugcomposition comprising 40 wt % nicardipine, 46.32 wt % polyethyleneoxide comprising a 200,000 molecular weight, 8.18 wt % polyethyleneoxide comprising a 200,000 molecular weight, 5.00 wt %hydroxypropylmethylcellulose comprising a 11,200 molecular weight and3.50 wt % magnesium stearate; a push composition comprising 73.50 wt %polyethylene oxide comprising a 7,000,000 molecular weight, 20.00 wt %sodium chloride, 5 wt % hydroxypropylmethylcellulose comprising a 11,200molecular weight, 1 wt % ferric oxide, and 0.50 wt % magnesium stearate;and a semipermeable wall comprising 93 wt % cellulose acetate and 7 wt %polyethylene glycol. The osmotic system is manufactured without asubcoat. The release rate for this dosage form through a 25 mil orificeis illustrated in FIG. 7, and the cumulative amount released isillustrated in FIG. 8.

In Table I, the osmotic system represented by FIG. 9 comprises a drugcomposition comprising 60 wt % verapamil hydrochloride, 30.50 wt %polyethylene oxide comprising 300,000 molecular weight, 4 wt %polyvinylpyrrolidone comprising a 40,000 molecular weight, 5 wt % sodiumchloride, and 0.50 wt % magnesium stearate; a push compositioncomprising 73.50 wt % polyethylene oxide comprising 7,000,000 molecularweight, 20.00 wt % sodium chloride, 5 wt % hydroxypropylmethylcellulosecomprising a 11,200 molecular weight, 1.00 wt % red ferric oxide and0.50% magnesium stearate; and a semipermeable wall comprising 60.00 wt %cellulose acetate comprising a 39.8% acetyl content, 35 wt %hydroxypropylcellulose, and 5 wt % polyethylene glycol. The dosage formcomprises four orifices of 25 mil diameter, and the dosage form is freeof an internal subcoat. The release rate for the osmotic system isillustrated in FIG. 9, and the cumulative amount released is illustratedin FIG. 10.

In Table I, the osmotic system represented by FIG. 11 comprises a drugcomposition comprising 60.00 wt % of verapamil hydrochloride, 30.50 wt %polyethylene oxide comprising a 300,000 molecular weight, 4.00 wt %polyvinylpyrrolidone comprising a 40,000 molecular weight, 5 wt % sodiumchloride and 0.50 wt % of magnesium stearate; a push compositioncomprising 73.50 wt % polyethylene oxide comprising a 7,000,000molecular weight, 20.00 wt % sodium chloride, 5.00 wt %hydroxypropylmethylcellulose comprising a 11,200 molecular weight, 1.00wt % red ferric oxide, and 0.50 wt % magnesium stearate; a subcoatcomprising 95.00 wt % hydroxyethylcellulose and 5.00 wt % polyethyleneglycol; and a semipermeable wall comprising 60.00 wt % cellulose acetatecomprising an acetyl content of 39.8%, 35.00 wt % hydroxyethylcellulosecomprising a 90,000 molecular weight and 5.00 wt % polyethylene glycol.The osmotic system comprises four orifices of 25 mil diameter. Therelease rate for the osmotic system is illustrated in FIG. 11, and thecumulative amount released is illustrated in FIG. 12.

Example 11

A series of dosage forms are prepared by following the above examples.In this example, the release rate for a dosage form manufactured free ofan internal subcoat is compared against the release rate for a dosageform manufactured with an internal subcoat. In accompanying FIG. 13, therelease rate for a dosage form manufactured free of a subcoat isillustrated in FIG. 13 by the line with clear squares, and the releaserate for a dosage form manufactured with a subcoat is illustrated inFIG. 13 by the line with dark squares. In FIG. 13, the dosage form freeof a subcoat comprises 60 wt % of verapamil hydrochloride, 30.50 wt %polyethylene oxide comprising a 300,000 molecular weight, 5.00 wt %polyvinylpyrrolidone comprising a 40,000 molecular weight, 4.00 wt %sodium chloride, and 0.50 wt % magnesium stearate; an expandable, pushcomposition in layered relation with the drug composition comprising73.50 wt % polyethylene oxide comprising a 7,000,000 molecular weight,20.00 wt % sodium chloride, 5.00 wt % hydroxypropylmethylcellulosecomprising a 11,200 molecular weight, 1.00 wt % ferric oxide, and 0.50wt % magnesium stearate; and a semipermeable wall comprising 65.00 wt %cellulose acetate comprising a 39.8% acetyl content, 30.00 wt %hydroxypropylcellulose and 5.00 wt % polyethylene glycol. The dosageform comprises four passageways, possesses a T-90 of 16.6 hours, a meanrelease rate of 12.874 mg/hr, a total drug 198.00 mg and a drug dose of180.00 mg.

The dosage form comprising an internal subcoat comprises 60.00 wt %verapamil hydrochloride, 30.50 wt % polyethylene oxide comprising a300,000 molecular weight, 5.00 wt % polyvinylpyrrolidone comprising a40,000 molecular weight, 4.00 wt % sodium chloride, and 0.50 wt %magnesium stearate; an expandable composition comprising 73.50 wt %polyethylene oxide comprising a 7,000,000 molecular weight, 20.00 wt %sodium chloride, 5.00 wt % hydroxypropylmethylcellulose comprising11,200 molecular weight, 1.00 wt % ferric oxide, and 0.50 wt % magnesiumstearate; a subcoat comprising the nonionic water-soluble polymerhydroxyethylcellulose present as 95 wt % in the subcoat, and 5.00 wt %polyethylene glycol 3350; and a semipermeable wall comprising 60.00 wt %cellulose.

Example 12

A series of dosage forms are prepared by following the above examples.In this example, the release for dosage forms manufactured without aninternal subcoat is compared against the release rate for a dosage formmanufactured with an internal subcoat. In accompanying FIG. 14, therelease rate for a dosage form manufactured without a subcoat isillustrated by the line comprising blank squares, while the release ratefor a dosage form manufactured with an internal subcoat is illustratedby the line with dark squares. In FIG. 14, the dosage form made withouta subcoat comprises a 330.0 mg drug layer, which drug layer comprises60.50 wt % verapamil hydrochloride, 30.50 wt % polyethylene oxidecomprising a 300,000 molecular weight, 5.00 wt % polyvinylpyrrolidone,4.00 wt % sodium chloride and 0.50 wt % magnesium stearate; apush-expandable layer comprising 110.0 ng, which latter layer comprises73.50 polyethylene oxide comprising a 7,000,000 molecular weight, 20.00wt % sodium chloride, 5.00 wt % hydroxypropylmethylcellulose comprisinga 11,200 molecular weight, 1.00 wt % ferric oxide, and 0.50 wt %magnesium stearate. The dosage comprises a semipermeable wall thatcomprises 60 wt % cellulose acetate comprising 39.8% acetyl content, 35wt % hydroxypropylcellulose comprising a 80,000 molecular weight and 5wt % polyethylene glycol 3350. The osmotic dosage form comprises twoorifices of 30 mil diameter and it has a mean release rate of 18.77mg/hr. This dosage form possesses a drug delay attributed to therate-controlling semipermeable wall and the polyethylene oxide in thedrug layer.

The dosage form comprising the internal initially drug-free subcoat,comprises a 330.0 mg drug layer, which drug layer comprises 60.00 wt %of verapamil hydrochloride, 30.50 polyethylene oxide comprising a300,000 molecular weight, 4.00 polyvinylpyrrolidone comprising a 40,000molecular weight, 5.00 wt % sodium chloride, and 0.50 wt % magnesiumstearate; a push layer weighing 110.0 mg and comprising 73.50 wt % ofpolyethylene oxide comprising a 7,000,000 molecular weight, 20.00 wt %sodium chloride, 5.00 wt % hydroxypropylmethylcellulose 11,200 molecularweight, 1.00 wt % ferric oxide, and 0.50 wt % magnesium stearate; aninitially drug free subcoat comprising 95 wt % hydroxyethylcellulose and5 wt % polyethylene glycol, which subcoat weighed 91.0 mg; and anexternal semipermeable wall 5.5 mils which, weighing 67.4 mg andcomprising 60 wt % cellulose acetate comprising 39.8% acetyl content, 35wt % hydroxypropylcellulose and 5 wt % polyethylene glycol. The diameterof the orifice is 30 mils, and a mean release rate of 18.76 mg/hr. Thedosage form possesses a delayed drug release period attributed to thesubcoat functioning in combination with the semipermeable wall and thepolymer in the drug layer. In accompanying FIG. 15, the release rate isdepicted for the osmotic dosage form manufactured without a subcoat; inFIG. 16, the cumulative amount released is depicted for the dosage formmanufactured without a subcoat; in FIG. 17, the release rate is depictedfor a dosage form made comprising a subcoat; and, in FIG. 18, thecumulative amount released is depicted from a dosage form made with asubcoat. Accompanying FIG. 19 depicts the drug delay from an osmoticdosage system comprising an internal subcoat comprising differentweights, wherein the semipermeable wall of the osmotic system comprises60 wt % cellulose comprising 39.8% acetyl content, 35 wt %hydroxypropylcellulose and 5 wt % polyethylene glycol 3380, wherein thethickness of the semipermeable wall is 5.5 mils thick. In FIG. 19, they-axis denotes the drug delivered in hours and the x-axis denotes theweight of the subcoat, wherein the subcoat compriseshydroxyethylcellulose.

METHOD OF PRACTICING THE INVENTION

A presently preferred embodiment of the invention pertains to a methodfor delivering a drug to a patient during a circadian cycle comprisingan active phase and a less active phase, wherein the method comprises:(A) orally admitting into the patient a dosage form comprising means fordelivering a drug during the active phase and means for providing adrug-free interval during the less active phase. The method comprises:(B) admitting into the patient a dosage form comprising: (1) a wall thatsurrounds and forms an internal compartment, said wall comprising acomposition for slowing the fluid flux through the wall; (2) a drugcomposition in the compartment, said composition comprising means fordelaying the delivery of drug from the dosage form; (3) a pushcomposition in the compartment for pushing the drug composition from thedosage form; (4) an orifice in the dosage form for delivering the drugfrom the dosage form; (B) imbibing fluid through the wall at a ratedetermined by the osmotic pressure gradient across the wall, therebycausing the drug composition to slowly form a dispensable compositionand the push composition to absorb fluid and push the dispensable drugcomposition from the dosage form; and, (C) delivering the drug after adrug-free interval to the patient. The invention provides also aninstant dose of drug by delivering a drug from an external instantrelease drug coat. In this delivery pattern, the instant release isfollowed by a drug-free interval. The method of the invention for thetreatment of hypertension and angina provides a drug-free interval whena patient is less active, that is, at rest or when asleep and theinvention provides drug during the rising or waking hours mainly duringthe time when activity reaches a maximum during the daytime hours.

The novel osmotic dosage form of this invention uses dual means for theattainment of precise release rate of drugs that are difficult todeliver in the environment of use, while simultaneously maintaining theintegrity and the character of the system. While there has beendescribed and pointed out features and advantages of the invention, asapplied to the presently preferred embodiments, those skilled in thedispensing art will appreciate that various modifications, changes,additions, and omissions in the system illustrated and described can bemade without departing from the spirit of the invention.

What is claimed is:
 1. A method for providing a drug to a patient duringthe morning hours, comprising: administering to the patient at bedtime adosage form for the delayed-delivery of the drug, the dosage formcomprising (1) a core including a drug useful in the treatment ofhypertension or angina, and (2) a layer substantially surrounding thecore, the layer comprising hydroxyethylcellulose having a molecularweight of 8500 to 4,000,000; the layer delaying the release of the drugfrom the core until the morning hours dependent upon the weight of thelayer to permit delivery of the drug at waking hours and to treathypertension or angina in the patient.